| 1. |
- Lau, Joey, et al.
(författare)
-
Oxygenation of islets and its role in transplantation
- 2009
-
Ingår i: Current Opinion in Organ Transplantation. - 1087-2418 .- 1531-7013. ; 14:6, s. 688-693
-
Forskningsöversikt (refereegranskat)abstract
- PURPOSE OF REVIEW: To summarize recent studies on the oxygenation of pancreatic islets and its role in islet transplantation. RECENT FINDINGS: Pancreatic islet cells are highly sensitive to hypoxic conditions. Hypoxia contributes to poor islet yield at isolation, as well as inflammatory events and cellular death during culture and early posttransplantation. Use of oxygen carriers, such as semifluorinated alkanes, during pancreas preservation and gas-permeable devices for islet culture and transport has in recent studies proven beneficial. Beta-cell death can be limited posttransplantation by targeting hypoxia-induced cellular pathways that cause apoptotic death. Owing to low revascularization, impaired oxygenation seems to prevail in intraportally transplanted islets. Means to improve revascularization, oxygenation and function of transplanted islets can be achieved not only by stimulating angiogenic factors, but also by decrease of angiostatic factors such as thrombospondin-1 in islets for transplantation. Moreover, bone-marrow-derived cells, such as mesenchymal stem cells and hematopoietic stem cells, can induce or contribute to increased revascularization. SUMMARY: Low oxygenation of islets contributes to cellular death and dysfunction during preparation of islets for transplantation, as well as posttransplantation. Interventions at these different steps to ensure adequate oxygenation have the potential to improve the results of clinical islet transplantation.
|
|
| 2. |
- Brandhorst, Heide, et al.
(författare)
-
New class of oxygen carriers improves islet isolation from long-term stored rat pancreata
- 2008
-
Ingår i: Transplantation Proceedings. - : Elsevier BV. - 0041-1345 .- 1873-2623. ; 40:2, s. 393-394
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Pancreas shipment is frequently associated with prolonged ischemia deteriorating islet graft function. The strategy to prevent ischemic damage utilizing perfluorodecalin (PFD) for human pancreas oxygenation does not seem to improve isolation outcome. The present study investigated the efficiency of perfluorohexyloctane (F6H8), a hyperoxygen carrier characterized by low specific density (1.33 g/cm3) and lipophilic qualities, to facilitate islet isolation from long-term stored rat pancreata. MATERIALS AND METHODS: Prior to islet isolation, pancreata were intraductally flushed in situ with Kyoto solution (KS) and stored for 24 hours in KS, oxygenated PFD, or F6H8. RESULTS: Islet isolation performed after 24-hour storage in KS failed completely. The intrapancreatic pO2 in PFD- and F6H8-incubated pancreata was almost the same. In correspondence, the ATP content and viability of isolated islets were similar as well. In contrast, islet yield and in vitro function were significantly reduced after storage in PFD compared with F6H8. CONCLUSION: This study suggested that islet isolation performed after long-term pancreas preservation can be significantly improved utilizing semifluorinated alkanes as oxygen carriers.
|
|
| 3. |
- Brandhorst, Heide, 1962-, et al.
(författare)
-
Perfluorohexyloctane improves long-term storage of rat pancreata for subsequent islet isolation
- 2009
-
Ingår i: Transplant International. - : Frontiers Media SA. - 0934-0874 .- 1432-2277. ; 22:10, s. 1017-1022
-
Tidskriftsartikel (refereegranskat)abstract
- Pancreas oxygenation by means of the hyperoxygen carrier perfluorodecalin (PFD) has been established to prevent ischemically induced damage from cold-stored pancreata. However, large-scale studies did not confirm the promising results that had been observed in smaller donor populations. This study assessed whether islet isolation from pancreata stored for prolonged periods can be improved by utilizing the new oxygen carrier perfluorohexyloctane (F6H8) characterized by lower gravity and higher lipophilicity than PFD. Subsequent to 24 h of storage in either oxygenated PFD or F6H8, the rat pancreata were assessed for the intrapancreatic partial oxygen pressure (pO(2)) and subsequently processed with current standard procedures. The intrapancreatic pO(2) was nearly identical in rat pancreata stored either in PFD or F6H8. Nevertheless, rat islet isolation outcome was significantly increased in terms of yield, integrity, in vitro function and post-transplant outcome after transplantation in diabetic nude mice when F6H8 was used as oxygen carrier. This proof-of-concept study demonstrated in rats that islet isolation performed after long-term storage of oxygenated pancreatic tissue can be significantly improved if PFD was replaced by F6H8.
|
|
| 4. |
|
|
| 5. |
- Christoffersson, Gustaf, et al.
(författare)
-
Clinical and Experimental Pancreatic Islet Transplantation to Striated Muscle : Establishment of a Vascular System Similar to that in Native Islets
- 2010
-
Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 59:10, s. 2569-2578
-
Tidskriftsartikel (refereegranskat)abstract
- Objective: Curing type 1 diabetes by transplanting pancreatic islets into the liver is associated with poor long-term outcome and graft failure at least partly due to inadequate graft revascularization. The aim of the current study was to evaluate striated muscle as a potential angiogenic site for islet transplantation. Research Design and Methods: The current study presents a new experimental model which is found applicable to clinical islet transplantation. Islets were implanted into striated muscle where after intra-islet vascular density and blood flow were visualized with intravital and confocal microscopy in mice, and by magnetic resonance imaging in three auto-transplanted pancreatectomized patients. Mice were rendered neutropenic by repeated injections of Gr-1 antibody and diabetes was induced by alloxan treatment. Results: Contrary to liver-engrafted islets, islets transplanted to mouse muscle were revascularized with vessel densities and blood flow entirely comparable to islets within intact pancreas. Initiation of islet revascularization at the muscular site was dependent on neutrophils, and the function of islets transplanted to muscle was proven by curing diabetic mice. The experimental data were confirmed in auto-transplanted patients where higher plasma volumes were measured in islets engrafted in forearm muscle compared to adjacent muscle tissue through high-resolution magnetic resonance imaging. Conclusions: This study presents a novel paradigm in islet transplantation whereby recruited neutrophils are crucial for the functionally restored intra-islet blood perfusion following transplantation to striated muscle under experimental and clinical situations.
|
|
| 6. |
- Danielsson, T, et al.
(författare)
-
Resistin increases islet blood flow and decreases subcutaneous adipose tissue blood flow in anaesthetized rats
- 2009
-
Ingår i: Acta Physiologica. - : Wiley. - 1748-1708 .- 1748-1716. ; 195:2, s. 283-288
-
Tidskriftsartikel (refereegranskat)abstract
- AIM: Resistin is an adipokine which has been suggested to participate in the induction of insulin resistance associated with type 2 diabetes. The aim of the present study was to investigate whether acute administration of resistin influences tissue blood perfusion in rats. METHODS: Resistin was administered as an intravenous infusion of 7.5 microg h(-1) (1.5 mL h(-1)) for 30 min to rats anaesthetized with thiobutabarbital. A microsphere technique was used to estimate the blood flow to six different depots of white adipose tissue (WAT), brown adipose tissue (BAT), as well as to the pancreas, islets, duodenum, colon, kidneys, adrenal glands and liver. RESULTS: Resistin administration led to an increased blood flow to the pancreas and islets and a decrease in subcutaneous WAT and BAT. Intra-abdominal white adipose tissue blood flow and that to other organs were not affected. CONCLUSION: Acute administration of resistin markedly affects the blood perfusion of both the pancreas and subcutaneous white adipose tissue depots. At present it is unknown whether resistin exerts a direct effect on the vasculature, or works through local or systemic activation of endothelial cells and/or macrophages. The extent to which this might contribute to the insulin resistance caused by resistin is yet unknown.
|
|
| 7. |
- Henriksnäs, Johanna, et al.
(författare)
-
Acute effects of Helicobacter pylori extracts on gastric mucosal blood flow in the mouse
- 2009
-
Ingår i: World Journal of Gastroenterology. - : Baishideng Publishing Group Inc.. - 1007-9327 .- 2219-2840. ; 15:2, s. 219-225
-
Tidskriftsartikel (refereegranskat)abstract
- AIM: To investigate the mechanisms underlying the reduction in gastric blood flow induced by a luminal water extract of Helicobacter pylori (HPE).METHODS: The stomachs of isoflurane-anesthetized mice were exteriorized, and the mucosal surface exposed. Blood flow was measured with the laser-Doppler technique, and systemic arterial blood pressure monitored. C57BL/6 mice were exposed to water extract produced from H pylori strain 88-23. To investigate the role of a nerve- or iNOS-mediated pathway, we used intraluminal lidocaine and iNOS-/- mice. Blood flow response to the endogenous nitric oxide synthase inhibitor asymmetric dimethyl arginine (ADMA) was also assessed.RESULTS: In wild-type mice, HPE decreased mucosal blood flow by approximately 30%. This reduction was abolished in iNOS-deficient mice, and by pre-treatment with lidocaine. Luminally applied ADMA resulted in reduction in blood flow similar to that observed in wild-type mice exposed to HPE.CONCLUSION: A H pylori water extract reduces gastric mucosal blood flow acutely through iNOS- and nerve-mediated pathways.
|
|
| 8. |
- Henriksnäs, Johanna, et al.
(författare)
-
An in vivo model for gastric physiological and pathophysiological studies in the mouse
- 2005
-
Ingår i: Acta Physiologica Scandinavica. - 0001-6772 .- 1365-201X. ; 184:2, s. 151-159
-
Tidskriftsartikel (refereegranskat)abstract
- Aim: In vivo models for studying gastrointestinal physiology and pathophysiology are well established in rats. Since a number of genetically modified mice are available there is a need for reliable mouse models. The aim of this project was to develop an in vivo mouse model for gastrointestinal studies. Methods: C57bl/6, NMRI and transgenic FVB/N (expressing human α-1,3/4-fucosyltransferase) mice were anaesthetized with isoflurane and the gastric mucosa exteriorized for intravital microscopy. Acid–base status and acid secretion were measured and blood pressure was continuously monitored. Gastric mucosal blood flow was recorded by laser-Doppler flowmetry. Mucus thickness and accumulation rate were measured with micropipettes. Results: We have developed an in vivo mouse model for studies of the gastric mucosa. With isoflurane anaesthesia the preparation can be studied for up to 5 h with stable blood pressure and mucosal blood flow. Acid–base status agrees with results from other laboratories. Blood flow increased in both C57bl/6 and α1.3/4-FT mice in response to luminal HCl, and the mucus gel could be divided into a firmly and a loosely adherent layer, all comparable with results in the rat. However, the firmly adherent mucus layer was thinner (45 ± 2 μm), and the mucus accumulation rate lower, than in the rat. Furthermore, both basal and stimulated acid secretion showed lower outputs than in the rat. Conclusions: This model has great potential for investigations of gastrointestinal physiology and pathophysiology and can be applied for Helicobacter pylori infection studies.
|
|
| 9. |
- Henriksnäs, Johanna, 1973-
(författare)
-
Helicobacter pylori and Gastric Protection Mechanisms : An in vivo Study in Mice and Rats
- 2005
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The stomach is frequently exposed to hazardous agents and to resist this harsh environment, several protective mechanisms exist. Of special interest is the gastric pathogen Helicobacter pylori which causes gastritis, ulcers and cancer but the mechanism leading to these diseases are still unclear. However it is very likely that H. pylori negatively influence the protection mechanisms that exist in the stomach. The aims of the present investigation were first to develop an in vivo mouse model in which different protection mechanisms could be studied, and second to investigate the influence of H. pylori on these mechanisms. An in vivo preparation of the gastric mucosa in mice was developed. This preparation allows studies of different gastric mucosal variables and can also be applied for studies in other gastro-intestinal organs. Mice chronically infected with H. pylori, were shown to have a reduced ability of the mucosa to maintain a neutral pH at the epithelial cell surface. This could be due to the thinner inner, firmly adherent mucus gel layer, and/or to defective bicarbonate transport across the epithelium. The Cl-/HCO3- exchanger SLC26A9 was inhibited by NH4+, which also is produced by H. pylori. The mRNA levels of SLC26A9 were upregulated in infected mice, suggesting a way to overcome the inhibition of the transporter. Furthermore, the hyperemic response to acid pH 2 and 1.5 was abolished in these mice. The mechanisms by which the bacteria could alter the blood flow response might involve inhibition of the epithelial iNOS.Water extracts of H. pylori (HPE) reduces the blood flow acutely through an iNOS and nerve-mediated pathway, possibly through the endogenous iNOS inhibitor ADMA. Furthermore, HPE alters the blood flow response to acid as the hyperemic response to acid pH 0.8 is accentuated in mice treated with HPE.
|
|
| 10. |
- Henriksnäs, Johanna, et al.
(författare)
-
Impaired mucus-bicarbonate barrier in Helicobacter pylori-infected mice
- 2006
-
Ingår i: American Journal of Physiology - Gastrointestinal and Liver Physiology. - : American Physiological Society. - 0193-1857 .- 1522-1547. ; 291:3, s. G396-G403
-
Tidskriftsartikel (refereegranskat)abstract
- To resist the harsh intrinsic milieu, several lines of defense exist in the stomach. The aim of this study was to investigate the effect of the gastric pathogen Helicobacter pylori on these mechanisms in vivo. We used FVB/N mice expressing human alpha-1,3/4-fucosyl transferase ( producing Lewis b epitopes) and inoculated with H. pylori 1. Mice were anesthetized with isoflurane or Hypnorm-midazolam, the stomach was exteriorized, and the surface of the corpus mucosa was exposed. Mucus thickness was measured with micropipettes, juxtamucosal pH (pH(jm)) was measured with pH-sensitive microelectrodes, blood flow was measured with laser-Doppler flowmetry, and mRNA levels of the bicarbonate transporter SLC26A9 were quantified with real-time PCR. The increase in mucosal blood flow seen in response to luminal acid (pH 1.5) in control animals (140 +/- 9% of control) was abolished in infected mice. The firmly adherent mucus layer was significantly thinner in infected mice (31 +/- 2 mu m) than in control mice (46 +/- 5 mu m), and no mucus accumulation occurred in infected mice. pHjm decreased significantly more on exposure to luminal acid in infected mice ( luminal pH 1.5, pH(jm) 2.4 +/- 0.7) than in control mice (pH(jm) 6.4 +/- 0.5). Despite reduced pHjm, SLC26A9 mRNA expression was significantly, by increased 1.9-fold, in infected mice. The reduction in pH(jm) by infection with H. pylori might be due to a reduced firmly adherent mucus layer, increased mucus permeability to H+, and/or inhibition of bicarbonate transport. The upregulation of SLC26A9 in H. pylori-infected epithelium might be a result of continuous inhibition of the transporter, e. g., by ammonium, a H. pylori product, which has been previously shown to inhibit SLC26A9.
|
|
